In offspring of pregnancies complicated by poorly controlled diabetes mellitus, intrauterine growth retardation and premature delivery, perturbations in systemic perinatal glucose homeostasis may adversely affect the central nervous system (CNS) milieu, predisposing the neonate to CNS injury. The thesis of this proposal is that systemic hypoglycemia and hyperglycemia result in circulatory, metabolic, and blood-brain barrier permeability changes, which may place the fetus and neonate at higher risk for hypoxic-ischemic injury, and/or other CNS injury. The specific aims of this proposal examine (1) the importance of prostanoids, (6-keto- prostaglandin F1alpha, thromboxane B2 and PGE2) to perinatal CNS circulation and metabolism during altered systemic glycemic states, (2) the importance of hypoglycemia to the development of ischemic CNS injury and (3) the importance of hyperglycemia to the development of ischemic CNS injury and (4) the effects of hyperglycemia on blood-brain barrier permeability in the early and late gestation fetus, cesarean-section delivered surfactant treated premature sheep and compare these findings to that of hyperglycemic full-term sheep. Studies will be performed in the chronically catheterized ovine fetus and neonate infused with insulin to induce hypoglycemia, glucose to induce hyperglycemia, insulin and glucose for a euglycemic hyperinsulinemic clamp and placebo for control fetuses. Fetal central nervous system blood flow (total and regional) will be measured with radionuclide-labelled microspheres, cerebral metabolism by the Fick principle, during steady- state conditions, by arterial-superior sagittal sinus differences of appropriate metabolites and blood-brain barrier permeability (total and regional) by the uni-directional influx of radiolabelled tracers (24Na, 14C-sucrose and 3H-mannitol) into brain. Pathophysiologic changes will be identified by comparing the results in the hypoglycemic or hyperglycemic fetuses to control, placebo-infused, fetal sheep. The overall goal of this proposal is to elucidate the CNS pathophysiology associated with perturbations in systemic glucose homeostasis.